Oral melphalan pharmacokinetics: influence of interferon-induced fever.
The influence of interferon-induced fever on oral melphalan pharmacokinetics has been studied in 10 myeloma patients in a randomized crossover design. The melphalan dose (0.25 mg/kg) was given alone and 5 hours after the administration of human interferon alpha (7 x 10(6) IU/m2), respectively. The plasma concentration of melphalan was determined by liquid chromatography with fluorometric detection after derivatization of melphalan with N-acetylcysteine. The area under the plasma concentration-time curve (AUC) was significantly lower (p = 0.02) when melphalan was given with interferon. There was a significant negative correlation (p = 0.008) between body temperature and dose normalized AUC, whereas no effect was noticed on the maximum plasma concentration (Cmax) and on the time to obtain Cmax. The rate of elimination showed a tendency (p = 0.06) to increase with increasing body temperature. It is suggested that the cytotoxicity of the drug is most probably enhanced because of the higher alkylating activity of the compound at elevated body temperatures.
Ehrsson
H
H
Karolinska Pharmacy and Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
Eksborg
S
S
Wallin
I
I
Osterborg
A
A
Mellstedt
H
H
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001831:Body Temperature; D004347:Drug Interactions; D005260:Female; D005334:Fever / Q000209:etiology / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D007370:Interferon Type I / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D011241:Prednisone / Q000008:administration & dosage
D007370:Interferon Type I; D008558:Melphalan; D011241:Prednisone